Project abstract This is a K08 career development award proposal from Lapo Alinari, MD, PhD, an Assistant Professor on Tenure Track in the Division of Hematology at the Ohio State University (OSU). Dr. Alinari will devote a minimum of 75% of his time to a focused research program on the role of transducin ?-like protein 1 (TBL1) in mantle cell lymphoma (MCL) and related translational research, with the remaining 25% served through 8 weeks of inpatient service. OSU has an internationally recognized hematologic cancer research program and the Division of Hematology has an excellent record of training successful physician-scientists. Dr. Alinari has a diverse mentoring team with a proven track record, including Dr. John C. Byrd (translational science), Dr. Natarajan Muthusamy (basic science, immunology), and Dr. Kevin Coombes (genomics/bioinformatics) to advise and support him in his research aims and career development plan. This team will be complemented by an advisory committee consisting of Dr. Robert A. Baiocchi (translational lymphoma) and Dr. Kristie A. Blum (clinical lymphoma). Dr. Alinari?s career development plan builds upon his prior research experience and includes formal coursework to further his knowledge of genomics, bioinformatics, immunology, drug development as well as professional development activities to enhance networking, improve manuscript/ grant writing skills with the goal of becoming an independent translational investigator focusing on MCL. MCL is an aggressive subtype of B-cell NHL which remains incurable. The Wnt/? catenin signaling pathway is aberrantly activated in many cancers including MCL, and promotes tumor cell survival through modulation of Wnt target genes. Targeting ? catenin has been unsuccessful due to the complexity of its structure and to the many off target effects of the compounds tested thus far. TBL1 is an E3 ubiquitin ligase that binds to ? catenin to promote its transcriptional activity. The objective of this research project is to functionally characterize the role of TBL1 in MCL, to validate TBL1 as a novel therapeutic target in preclinical models of this disease, and to study the molecular mechanism through which tegatrabetan, a small molecule inhibitor of TBL1, induces MCL cell death. The rationale is that the critical role of TBL1 as a transcriptional modulator is unexplored in MCL. Dr. Alinari?s preliminary data show that, in contrast to normal immune cells, MCL cells express high nuclear levels of TBL1 and are exquisitely sensitive to TBL1 inhibition, suggesting TBL1 is a potential novel therapeutic target in this disease. The central hypothesis is that TBL1 promotes the uncontrolled proliferation and survival of MCL cells through its dual ability to activate transcription of Wnt/? catenin target genes while repressing transcription of tumor suppressor/regulatory genes and that TBL1 inhibition via tegatrabetan will promote MCL cell death through modulation of the TBL1 transcriptional program. The work accomplished here will provide data on TBL1 function in MCL and promote the clinical development of tegatrabetan. Data obtained from these preclinical studies will be used to apply for additional funding to support a phase I clinical trial with tegatrabetan in MCL patients.